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Soft Tissue Sarcoma Pathology and Dermatopathology FAQ
I am the founder of bone/soft tissue sarcoma pathology and dermatopathology discussion groups on Facebook. I also actively use Twitter to discuss these topics. This is an actively-growing compilation of my answers and comments to frequently asked questions on these topics. DISCLAIMER: This is not medical advice or an official consultation. These are just general comments that represent my personal views and experiences on these topics. I may be wrong about some of these things. Some of my views may (and hopefully will) change over time. These comments are for educational purposes only and should never be used for patient care in place of peer-reviewed references and your own clinical judgement. Jerad M Gardner, MD Special thanks to my medical student Julie M Youngs for organizing and editing this page for me. General Comments and Questions * For comprehensive Dermatopathology textbooks, McKee is my favorite because it has many great pictures, but it is expensive. Weedon is also great. For introductory dermpath books try "Practical Dermatopathology" by Ronald Rapini, "Dermatopathology by First Impression" by Christine Ko, and "Requisites in Dermatology: Dermatopathology" by Dirk Elston. Q: What is on your differential for rhabdoid cell-type neoplasms? A: Here are some rhabdoid things I have seen in skin and soft tissue: melanoma, carcinoma, rhabdomyosarcoma, myoepithelioma or myoepithelial carcinoma (co-expression of S100 plus keratin), proximal type epithelioid sarcoma, malignant extra-renal rhabdoid tumor, poorly differentiated synovial sarcoma, and rhabdomyoma. There are others but those are just a few off the top of my head that I have personally seen. Q: When do you use MDM2 for diagnosis? A: For MDM2 (or CDK4, CPM1, etc), here is when I like to order it: * (1) a retroperitoneal mature fatty tumor with no atypia at all (if MDM2 is negative, it is likely retroperitoneal lipoma) * (2) a soft tissue tumor that looks like lipoma but is very large (greater than 10 cm), or has recurred multiple times, or has possible atypia that is not clear cut enough to be diagnostic of WDL/ALT * (3) a retroperitoneal mass that looks like myxoid liposarcoma (that is such an unusual location for MLS, and WDL in retroperitoneum can look exactly like MLS), and * (4) looks like a pleomorphic lipoma but in the wrong location, wrong age, or is very large. In summary, MDM2 is very useful for difficult cases where WDL is suspected but where the histologic features are not perfect. I prefer the FISH to the IHC. During fellowship, we ordered FISH for MDM2 more than any other soft tissue FISH. Adipocytic tumors are much more common than other soft tissue neoplasms. Alveolar Soft Part Sarcoma General comments on appearance and identification: * Notched "bite cells" are typical of ASPS, as well as cellular areas lacking alveolar architecture having a very zellballen appearance and looking an awful lot to me like paraganglioma. People don't usually talk about ASPS and paraganglioma being in the differential with one another, but I think you should always at least think about the possibility of a non-alveolar area of ASPS whenever you think you have a paraganglioma or see zellballen pattern (obviously once you see alveolar spaces it clearly can't be paraganglioma). I actually just recently learned that one of the old obsolete names for ASPS was "malignant nonchromaffin paraganglioma." * The abundant, dense pink cytoplasm of ASPS can call to mind pleomorphic rhabdomyosarcoma, epithelioid soft tissue tumors, and RCC or other carcinomas, and doing immunostains to exclude those is probably a good idea in general if you have any doubt about the diagnosis. I've personally never seen a pleomorphic rhabdomyosarcoma with an alveolar architecture like ASPS has. Pleomorphic rhabdo is usually strikingly pleomorphic and floridly mitotically active, way more so than ASPS would be. And I often hear people mention alveolar rhabdomyosarcoma whenever I show a case of ASPS during a lecture. Take a quick second to google image search alveolar rhabdomyosarcoma. Seriously...go do it right now. See the difference? Alveolar RMS is always a ROUND BLUE cell tumor. It does make alveolar spaces usually, but the cytology is completely different. Because it is a translocation sarcoma the nuclei are going to be uniform and monotonous, not pleomorphic (for this same reason ASPS usually has monotonous nuclei albeit with big central nucleoli also). Atypical Fibroxanthoma Q: How do you confirm a diagnosis of AFX? A: If ugly spindle cells are found in the dermis of old, sun-damaged skin, I do S100, p63, and pancytokeratin. If all are negative, I call AFX, provided it does NOT invade the subcutis. If it invades subcutis I classify it as superficial undifferentiated pleomorphic sarcoma since once in the subcutis, a lesion has metastatic potential (Fletcher calls these pleomorphic dermal sarcomas, if I understand correctly, but I think that name is confusing). But If it is a shave that is transected at the base, as it almost is, I will call AFX and add a comment that UPS could look and stain identically, and examination of excision specimen to exclude subcutis extension is essential. I don't need any positive marker for AFX/UPS as none of them are specific anyway. I just make sure I've excluded other possibilities. Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma (ALT-WDL) General comments: * Sharon Weiss taught me that if you are having difficulty finding atypical cells in a suspected case of ALT/WDL, look around the blood vessels. They often are located there. Q: What is the difference between ALT and WDL? A: They are identical tumors histologically and molecularly, but with very different outcomes. If they are located in the retroperitoneum, mediastinum, or spermatic cord/inguinal canal, I call them WDL. They will usually recur multiple times and eventually kill the patient (if they don't die of something else first... this is usually a disease of elderly and recurrences/dedifferentiation may happen over a period of 10-20 years). If they are located in the subcutis or in deep muscle of an extremity they usually are cured by excision and only rarely have dedifferentiation. We call them ALT in those locations because death from disease in those sites is rare. By itself, ALT/WDL does not ever metastasize unless it first dedifferentiates. But multiple bulky recurrences in the retroperitoneum can eventually compromise vital structures by mass effect and cause mortality. Q: Do you ever use CD10 in diagnosing AFX? A: CD10 stains everything. Seriously, if it is spindled, it will probably stain with CD10. Normal dermis often has abundant background staining. In the world of soft tissue tumors, I find CD10 next to vimentin in regards to it's usefulness (ie - almost completely worthless...see this satire video about vimentin: https://www.youtube.com/watch?v=UDnp14nnNC4 ). It may play an important role in other specialties like gyn or GU or hemepath, but not in soft tissue in my opinion. I know it stains AFX, but contrary to previous reports, I have often seen it stain SCC and spindle melanoma as well as cutaneous PEComa, angiosarcoma, and many other things. Cellular Neurothekeoma Q: What stains do you use for cellular neurothekeoma? A: For me, if it looks like cellular neurothekeoma I feel comfortable making diagnosis once other things (like melanocytic) are excluded. So usually if s100 is negative I don't pursue additional markers like NSE, PGP 9.5, NKI/C3. All of those are sensitive but very non specific so I don't feel like they help me very much in confirming the diagnosis. Chondroid Syringoma, Mixed Tumor Q: What mutation is characteristic of these tumors? A: Myoepithelial and mixed tumors of salivary origin often have PLAG1 mutations whereas those of soft tissue tend to have EWS rearrangements. The literature is mixed (no pun intended) regarding these lesions in the skin. Some suggest they are more akin to salivary ones molecularly, whereas others say they are like the soft tissue ones. I think more studies are needed to help sort this out more clearly. Dermatofibrosarcoma Protuberans (DFSP) Q: When do you do molecular testing (FISH, RT-PCR) to confirm t(17;22) COL1A1-PDGFB gene fusion in DFSP? A: I usually only do FISH for t(17;22) in cases where: 1. I suspect DFSP but am not certain or 2. I am pretty sure something is NOT DFSP but I still feel worried that I'm missing it (so I do the FISH to sleep well at night in that case). If I had a small biopsy from a skin mass that looked like "fibrosarcoma" (cellular and herringbone) but no obvious DFSP component and IHC were negative for S100 and keratin, I would probably call it "sarcoma, not further classified", raise differential diagnosis of fibrosarcomatous DFSP in the comment, and state that further classification will be based on complete excision specimen. I've never seen a case personally where there was no DFSP component at all on the complete excision specimen. Fibrosarcoma Q: Can fibrosarcoma be identified by herringbone fascicular pattern? A: Lots of things have herringbone fascicular pattern and most of those entities are NOT fibrosarcoma (examples include MPNST, synovial sarcoma, dedifferentiated liposarcoma, cellular schwannoma, mesoblastic nephroma, melanoma, etc). Fibrosarcoma is a vanishingly rare entity and diagnosis of exclusion. About the only time I ever use that word is: (1) when it is part of the name of a specific entity (e.g. dermatofibrosarcoma protuberans, sclerosing epithelioid fibrosarcoma) OR (2) for fibrosarcoma arising in DFSP OR (3) infantile fibrosarcoma. And both 2 and 3 can be confirmed by molecular testing if needed. Aside from that I advise my trainees to never use the term "fibrosarcoma." Hemangioendothelioma General comments: * I just want to point out one confusing thing. There are a handful of different types of hemangioendothelioma (epithelioid HE, kaposiform HE, ES-like (pseudomyogenic) HE, Dabska type HE, retiform HE, composite HE). Although they are all blood vessel tumors that have "intermediate" behavior (not always acting like full-blown cancer but also not fully benign) and all have "hemangioendothelioma" as part of their name, they are otherwise unrelated. They have different molecular/genetic causes, look different microscopically, and present and behave differently in patients. So they are a group of different diseases that share the HE name rather than one disease with several different subtypes. I know this is confusing for most pathologists even, so if it seems hard to grasp, you are in good company! But it makes a big difference sometimes as some of these (like EHE) tend to behave much worse than the others. Leiomyosarcoma Q: Can leiomyosarcoma be epithelioid in appearance and on IHC? A: Leiomyosarcoma can be epithelioid. Focal actin staining can be positive, but can also be seen in many other things and is not specific. Try staining with desmin. If desmin is negative, the only way I will call something leiomyosarcoma is if there is very strong diffuse actin expression. Liposarcoma General comments: * Dedifferentiated liposarcomas, despite being high grade, often have a longer course than other high grade sarcomas, with local recurrence being more of an issue than distant metastases in many cases. They almost all result in death eventually due to their impossible location for complete surgical resection. Malignant Peripheral Nerve Sheath Tumor Q: What is the S100 staining pattern for MPNSTs? A: MPNST is negative for S100 in about 50% of cases and is only weak and patchy positive in the other 50%. Rarely ever is it strongly S100 positive, with the exception of epithelioid MPNST. Also, I don't make a definitive diagnosis of MPNST outside of one of these three settings: (1) sarcoma arising in a nerve, (2) sarcoma arising in a neurofibroma or other benign nerve sheath tumor, or (3) sarcoma arising in a patient with Neurofibromatosis 1. Merkel Cell Carcinoma Q: What are the staining patterns of Merkel Cell? A: Although dot-like CK20 is the buzzword, it doesn't have to be dot-like, it can be diffuse. Also, other keratins like AE1/3 can have a dot-like pattern in Merkel. Neurofilament also works nicely as it stains most Merkel cells and is negative in most other neuroendocrine carcinomas. Q: How do you distinguish Merkel from BCC using IHC? A: If I think a case is BCC but just want to be sure it's not Merkel (i.e. low index of suspicion), I'll do CK20 and just sign it out as BCC if negative. If it looks classic for Merkel, I usually also just do CK20 alone. If positive, I sign it out as Merkel. If CK20 is negative, but I'm still pretty concerned about Merkel morphologically, I might pursue further with additional stains like CK7, synaptophysin, chromogranin, and neurofilament. If 7 and 20 are both negative, be sure to do a pancytokeratin to prove that it truly is carcinoma (remember, CK7 + CK20 ≠ PanCK!). You might also consider doing S100 to rule out small cell melanoma (I see melanoma all the time and almost never have seen one that looked much like Merkel, but it's theoretically possible). TTF-1 is used by some, but I would urge caution. It is very sensitive for small cell carcinoma of the lung but it is not totally specific, as it can be seen in pretty much any neuroendocrine carcinoma, even away from the lungs. So if TTF-1 is negative (and even better, if CK7 is also negative), you can be pretty sure that it is not small cell lung carcinoma. If TTF-1 is positive, I would raise the possibility of metastatic small cell carcinoma in my report and then they can scan the patient and look for a lung mass. I have still NEVER seen even one example of small cell lung carcinoma metastatic to the skin (nor have any of the pathologists who I've asked)...if you see one, send me a pic! NSE is very non-specific and I never use it. I also don't usually use CDX2 in this setting. Molluscum Contagiosum Q: How do you distinguish molluscum from myrmecia? A: Molluscum usually doesn't occur on actual sites nor will it be as large or of as long duration as a verruca. On H&E, molluscum has viral bodies that are relatively uniform in size whereas myrmecia wart has viral aggregates of varying size and shape as well as large chunky purple hypergranulosis and a papillomatous architecture. Mycosis Fungoides Q: How do you confirm MF in uncertain cases? A: The absolutely most important thing there is to ask the dermatologist: (1) is there a proven history of MF or if not, then (2) does background skin AWAY from nodules look like patch or plaque stage MF. If so, then biopsy those areas and try to find more obvious MF. Cellular nodules of atypical T cells in skin can definitely be tumor MF but could be other things too like LYP, ALCL, etc. The history and clinical correlation is essential. Also beware as the clinician or chart may say "biopsy proven history of MF" from an outside hospital, but then once you actually review that material is just another nodule like you have now that was called MF without clinical correlation. We see this often. Myofibroma Q: What are the characteristics of adult solitary myofibroma? A: Myofibroma was originally described as multiple tumors occurring in young kids (myofibromatosis). But we now know they are often solitary and can commonly occur in adults too. Histology shows two zones: (1) myoid nodules which often have a bluish "pseudochondroid" appearance and (2) cellular areas between nodules composed of bland spindle cells with ectatic staghorn vessels. IHC is not usually needed. These are totally benign and rarely recur even if margins are positive. Some myofibromas can be quite cellular and have lots of mitoses but still behave well. General comments: * There are three clinical forms: (1) a single skin or subcutaneous nodule, most common, often on the head or neck but can be anywhere, (2) multiple skin, subcutaneous, or bone nodules, with good prognosis, and (3) generalized with the internal organs also involved. The last has a poor prognosis and is usually seen in infants and kids, but is commonly seen in adults too. * There are two morphologic zones in these tumors: (1) myoid nodules often with a “pseudochondroid” appearance (even though they are myofibroblastic, I think the nodules look very bluish and chondroid, which confuses many pathologists), and (2) cellular zones of bland spindle cells with staghorn vessels, usually between the nodules. These have "atypical features"--high cellularity, minimal myoid nodules, increased mitosis, and may have necrosis but no usually no pleomorphism. They may be confused with sarcoma, yet these "atypical" features have uniformly good prognosis (don't overdiagnose). * IHC is usually not needed to identify these, but they are actin positive and usually desmin negative. * There is no routinely useful positive molecular finding. * Prognosis is generally good, as even with incomplete excision recurrence is rare. The exception is with internal organ involvement in the generalized form. Myxofibrosarcoma Q: Where are these tumors found? A: These are essentially myxoid variants of undifferentiated pleomorphic sarcoma. Typically they arise in the subcutis (or deep muscle) on the extremities of elderly adults Q: Do you use IHC in the diagnosis of myxofibrosarcoma? A: I usually do not do any IHC for myxofibrosarcoma unless there is something unusual about it. IHC almost never helps in those cases, and the only other thing that really looks much like it is myxoinflammatory fibroblastic sarcoma, or perhaps myxoid areas of pleomorphic liposarcoma, but IHC doesn't help much with either of those. Myxoid Lipsarcoma Q: How do you describe myxoid liposarcoma morphologically? A: I like "chicken feet" or "delicate branching/plexiform" vessels as descriptors, personally. I also point out to residents that the vessels of myxoid liposarcoma are very very thin, with a wall that is about one endothelial cell thick and a lumen that allows about one red cell through at a time. Many other things have branching vessel pattern, but not many have such delicate vessels. Nerve Sheath Myxoma ("Conventional" Neurothekeoma) Q: What is the relationship between nerve sheath myxoma (conventional neurothekeoma) and cellular neurothekeoma? A: They are not related in my opinion. Nerve sheath myxoma (previously known as "conventional" neurothekeoma) is a benign nerve sheath tumor likely related to schwannoma. I currently only use the "neurothekeoma" term to refer to cellular neurothekeoma, which interestingly is not related to this entity nor is it even a nerve sheath tumor (unknown histologic line of differentiation...maybe myofibroblastic or fibrohistiocytic). The terminology here is very vexing and makes literature (even recent literature) challenging to interpret sometimes. Regarding IHC for this differential, I usually just use s100. It is positive always in nerve sheath myxoma but always negative in cellular neurothekeoma. Cellular neurothekeoma is also positive for a wide range of markers but they are all non-specific so I don't generally use them (MiTF, NKI-C3, NSE, S100 A6, etc). Neurofibroma Q: Are Wagner-Meissner bodies specific for diffuse neurofibroma? A: Wagner-Meissner bodies are classically seen in diffuse neurofibroma, although I've seen them in other things, particularly neurotized nevus. I've also made a diagnosis of diffuse neurofibroma without WM bodies just based on infiltrative growth in the subcutis. Q: What are the criteria for plexiform neufibroma? A: Plexiform neurofibroma should only be diagnosed when the gross appearance of the mass has the classic "bag of worms" appearance. Even if there is low power multinodular appearance, I am very wary of diagnosing plexiform neurofibroma without the classic gross findings or a known history of NF-1. The reason for such strict criteria is that by diagnosing plexiform neurofibroma, you are essentially giving the patient NF-1, a heritable genetic disease with a significant risk of transmission to their offspring and a significant lifetime risk of developing sarcoma (MPNST). It's a benign tumor, but the implications for the patient are enormous. So I'm always very cautious here. Nuchal Type Fibroma & Gardner Fibroma General comments: * Dense collagen and few spindle cells makes me think of nuchal type fibroma. Posterior neck in a young MALE patient is a good clinical setting for it. Gardner fibroma (associated with FAP colon cancer syndrome) looks very similar but usually presents in childhood. Rosai-Dorfman Disease General comments: * I think you can routinely and reliably make the diagnosis from 2x magnification in most cases without needing to look at high power for emperipolesis (I always do look anyway, but learning how to diagnose from 2x is a good skill). My former fellow loved to say "Pink and blue, baby!" because that is precisely what you want to see at 2x: sheets of big pink cells with multiple blue lymphoid aggregates. At higher power, you will see big histiocytes with large clear vesicular nuclei and prominent nucleoli, many plasma cells, and emperipolesis. S100 stains these tumors nicely and highlights the vacuoles containing inflammatory cells (these cells are intact and whole, unlike hematophagocytosis where the cells are being destroyed in the histiocytes and there is karyorrhexis), but I do not routinely do S100. This is an H&E diagnosis. RDD often resolves on its own usually within a few years. Q: Is emperipolesis necessary for the diagnosis of Rosai-Dorfman? A: I feel emperipolesis gets a lot more weight than it should. I don't require it for diagnosis of RDD. If I see alternating pink sheets of pale histiocytes and blue lymphoid aggregates from low power and then see large histiocytes with big vesicular nuclei, prominent nucleoli, and abundant pale cytoplasm at high power...those things are enough to call RDD for me. The histiocytes' nuclei are so distinct and unique that they confirm the diagnosis for me in most cases. If I'm unsure, I'll add A100 and hunt around for emperipolesis. Schwannoma General comments: * Unlike neurofibromas, schwannomas rarely undergo malignant transformation. When they do become malignant, two of the patterns seen are (1) angiosarcoma arising in schwannoma and (2) small round blue cell sarcoma (Ewings/PNET like) arising in schwannoma. Sclerosing Epithelioid Fibrosarcoma Q: How do you confirm a diagnosis? A: Sclerosing epithelioid fibrosarcoma is a serious diagnosis as about 40% of cases get metastases. Muc4 stain and FISH for EWS are helpful ways to confirm it. Spindle Cell Lipoma Q: How do you distinguish the low-fat variant of spindle cell lipoma from fibromyxoid sarcoma and other translocation sarcomas? A: These tumors are often very myxoid which raises lots of bad tumors in the differential diagnosis and prompts a consult. The vague palisading ("parallel arrays of nuclei") is a very useful feature. Low grade fibromyxoid sarcoma is always a great thing to think of in a case like this as it usually lacks mitotic activity and pleomorphism (translocation sarcomas are usually monotonous, not pleomorphic!). However, palisading, small size, focal adipocytes, ropey collagen, and a uniformly myxoid appearance present can distinguish spindle cell lipoma from LGFMS. Squamous Cell Carcinoma Q: How do you determine between SCC and reactive changes in a lesion with some atypia and extensive involvement? A: These cases can be hard to decide. I would do stains for invasive fungus, polarize the tissue for foreign bodies, check the dermis to make sure there is no underlying granular cell tumor - all could cause changes like this. Then I would call clinician to discuss. I had case like this before that looked very much like SCC but patient had extensive leg involvement. Clinical pics and discussion with dermatologist swayed us to favor stasis with reactive epithelial hyperplasia over SCC. They were considering amputation if we had called it SCC. Fortunately that was avoided and patient began to improve on conservative therapy. Really eye opening case! Synovial Sarcoma Q: Can the FNCLCC grading system be applied to synovial sarcoma? A: FNCLCC grading works well for many but not all sarcomas. Synovial sarcoma can indeed have very bland areas with low mitoses that would be technically FNCLCC Grade 1. But grade is not a very good predictor of behavior for synovial sarcoma. Better prognostic factors are size, depth/location, and presence of poorly differentiated (round blue cell or large epithelioid cell) components. Tendon Sheath Fibroma Q: What are the morphologic features of tendon sheath fibroma? A: A classic example of fibroma of tendon sheath is a circumscribed nodule with a dense collagenous background, scattered bland spindle cells, and cleft-like vessels as well as cleft-like cracking artifact of the collagen. Older, mature lesions have these features, whereas "younger," more cellular lesions look very much like nodular fasciitis, a variant called "cellular fibroma of tendon sheath." If you see something like nodular fasciitis on an acral site, is is very probably cellular fibroma of tendon sheath instead. Trichoblastic Carcinoma Q: Are trichoblastic carcinoma and basal cell carcinoma the same thing? A: I used to think they were the same thing, but I've since seen two situations where I think the term trichoblastic carcinoma is appropriate: (1) a tumor that looks like trichoblastoma and has bland cytology, but also has infiltrative growth and/or aggressive clinical behavior, and (2) a high grade carcinoma that doesn't really look like typical BCC, arising out of what looks obviously like a benign trichoblastoma (sort of a carcinoma ex trichoblastoma if you will). To me, both of those situations clearly look trichoblastic in origin, clearly are malignant, and yet clearly are not BCC, thus I have nothing else to call them aside from trichoblastic carcinoma. I think my colleague and I have collectively used that term maybe 3 times since we both started practice 2 years ago, and we see a lot of odd consult cases aside from our everyday case load. Trichoepithelioma & Trichoblastoma Q: How do you distinguish trichoepithelioma from trichoblastoma? A: The distinction is merely academic in my opinion, as both are benign follicular tumors. Also, in my experience it seems like follicular tumors exist on a spectrum and show overlapping features often. Rapini says it is easier to classify snowflakes than follicular tumors! I tend to call it trichoepithelioma in these settings: * when it is a relatively small superficial lesion * when basaloid nests are small * when there is abundant cellular stroma between nests with nice papillary mesenchymal bodies I tend to call it trichoblastoma in these settings: * when it is larger and deeper * when there are large nests or sheets of basaloid cells * when there is a trabecular/rippled pattern * when the cellular stroma is less pronounced and papillary mesenchymal bodies are less obvious Ackerman, if I understand his views correctly, believed that trichoepithelioma is merely a variant of trichoblastoma. Verrucous Carcinoma Q: What are the morphologic differences between VC and SCC? A: It cannot be verrucous carcinoma if there is marked atypia. My understanding from my oral pathology colleagues is that by definition, verrucous carcinoma has minimal nuclear atypia. Verrucous surface profile, parakeratosis, broad bulbous rete with pushing invasion of the dermis, and increased mitoses along the basal layer are all features of verrucous carcinoma, but nuclear atypia must be minimal. If there is marked atypia, it is better classified as SCC. Xanthogranuloma (JXG) *I've seen a few cases of early JXG that really resembled mastocytosis at low power. I had never before realized that those entities could mimic one another.